title: Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo.
abstract: Deubiquitinases (DUBs) are proteases that regulate various cellular processes by controlling protein ubiquitination. Cell-based studies indicate that the regulation of the activity of DUBs is important for homeostasis and is achieved by multiple mechanisms, including through their own ubiquitination. However, the physiological significance of the ubiquitination of DUBs to their functions in vivo is unclear. Here, we report that ubiquitination of the DUB ataxin-3 at lysine residue 117, which markedly enhances its protease activity in vitro, is critical for its ability to suppress toxic protein-dependent degeneration in Drosophila melanogaster. Compared with ataxin-3 with only Lys-117 present, ataxin-3 that does not become ubiquitinated performs significantly less efficiently in suppressing or delaying the onset of toxic protein-dependent degeneration in flies. According to further studies, the C terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase that ubiquitinates ataxin-3 in vitro, is dispensable for its ubiquitination in vivo and is not required for the neuroprotective function of this DUB in Drosophila. Our work also suggests that ataxin-3 suppresses degeneration by regulating toxic protein aggregation rather than stability.
authors.affiliation: From the Departments of Pharmacology and Neurology and.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Tsou
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Burr
authors.forename: Michelle
authors.initials: M
authors.lastname: Ouyang
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Blount
authors.forename: K Matthew
authors.initials: KM
authors.lastname: Scaglione
authors.forename: Sokol V
authors.initials: SV
authors.lastname: Todi
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008239:Lysine / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010858:Pigmentation / Q000235:genetics; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C108740:Chi protein, Drosophila; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D064570:Ubiquitin-Specific Proteases; D008239:Lysine
keywords: Ataxin-3; Deubiquitination; Drosophila; Machado-Joseph Disease; Neurodegeneration; Neuroprotection; Polyglutamine Disease; Protease; Ubiquitin